A historical perspective on clonidine as an alpha-2A receptor agonist in the treatment of addictive behaviors: Focus on opioid dependence.

Clonidine operates through agonism at the alpha-2A receptor, a specific subtype of the alpha-2-adrenergic receptor located predominantly in the prefrontal cortex. By inhibiting the release of norepinephrine, which is responsible for withdrawal symptoms, clonidine effectively addresses withdrawal-related conditions such as anxiety, hypertension, and tachycardia. The groundbreaking work by Gold et al. demonstrated clonidine's ability to counteract the effects of locus coeruleus stimulation, reshaping the understanding of opioid withdrawal within the field. In the 1980s, the efficacy of clonidine in facilitating the transition to long-acting injectable naltrexone was confirmed for individuals motivated to overcome opioid use disorders (OUDs), including physicians and executives. Despite challenges with compliance, naltrexone offers sustained blockade of opioid receptors, reducing the risk of overdose, intoxication, and relapse in motivated patients in recovery. The development of clonidine and naltrexone as treatment modalities for OUDs, and potentially other addictions, including behavioral ones, underscores the potential for translating neurobiological advancements from preclinical models (bench) to clinical practice (bedside), ushering in innovative approaches to addiction treatment.

Selenoprotein P in a Rodent Model of Exercise; Theorizing Its Interaction with Brain Reward Dysregulation, Addictive Behavior, and Aging.

Exercise promotes health and wellness, including its operation as a protective factor against a variety of psychological, neurological, and chronic diseases. Selenium and its biomarker, selenoprotein P (SEPP1), have been implicated in health, including cancer prevention, neurological function, and dopamine signaling. SEPP1 blood serum levels were compared with a one-way ANOVA between sedentary (SED), moderately exercised (MOD) [10 m/min starting at 10 min, increasing to 60 min], and high-intensity interval training (HIIT) exercised rats [30 min in intervals of 2-min followed by a 1-min break, speed progressively increased from 10 to 21 m/min]. HIIT rats showed significantly higher serum SEPP1 concentrations compared to MOD and SED. More specifically, HIIT exercise showed an 84% increase in SEPP1 levels compared to sedentary controls. MOD rats had greater serum SEPP1 concentrations compared to SED, a 33% increase. The results indicated that increased exercise intensity increases SEPP1 levels. Exercise-induced increases in SEPP1 may indicate an adaptive response to the heightened oxidative stress. Previous studies found a significant increase in dopamine D2 receptor (D2R) binding in these same rats, suggesting a potential association between SEPP1 and dopamine signaling during exercise. Modulating antioxidants like SEPP1 through personalized therapies, including exercise, has broad implications for health, disease, and addiction.

Colon impairments and inflammation driven by an altered gut microbiota leads to social behavior deficits rescued by hyaluronic acid and celecoxib.

BACKGROUND: The exact mechanisms linking the gut microbiota and social behavior are still under investigation. We aimed to explore the role of the gut microbiota in shaping social behavior deficits using selectively bred mice possessing dominant (Dom) or submissive (Sub) behavior features. Sub mice exhibit asocial, depressive- and anxiety-like behaviors, as well as systemic inflammation, all of which are shaped by their impaired gut microbiota composition. METHODS: An age-dependent comparative analysis of the gut microbiota composition of Dom and Sub mice was performed using 16S rRNA sequencing, from early infancy to adulthood. Dom and Sub gastrointestinal (GI) tract anatomy, function, and immune profiling analyses were performed using histology, RT-PCR, flow cytometry, cytokine array, and dextran-FITC permeability assays. Short chain fatty acids (SCFA) levels in the colons of Dom and Sub mice were quantified using targeted metabolomics. To support our findings, adult Sub mice were orally treated with hyaluronic acid (HA) (30 mg/kg) or with the non-steroidal anti-inflammatory agent celecoxib (16 mg/kg). RESULTS: We demonstrate that from early infancy the Sub mouse gut microbiota lacks essential bacteria for immune maturation, including Lactobacillus and Bifidobacterium genera. Furthermore, from birth, Sub mice possess a thicker colon mucin layer, and from early adulthood, they exhibit shorter colonic length, altered colon integrity with increased gut permeability, reduced SCFA levels and decreased regulatory T-cells, compared to Dom mice. Therapeutic intervention in adult Sub mice treated with HA, celecoxib, or both agents, rescued Sub mice phenotypes. HA treatment reduced Sub mouse gut permeability, increased colon length, and improved mouse social behavior deficits. Treatment with celecoxib increased sociability, reduced depressive- and anxiety-like behaviors, and increased colon length, and a combined treatment resulted in similar effects as celecoxib administered as a single agent. CONCLUSIONS: Overall, our data suggest that treating colon inflammation and decreasing gut permeability can restore gut physiology and prevent social deficits later in life. These findings provide critical insights into the importance of early life gut microbiota in shaping gut immunity, functionality, and social behavior, and may be beneficial for the development of future therapeutic strategies.